FUNCTION AND SIGNAL TRANSDUCTION OF METABOTROPIC GLUTAMATE RECEPTOR 1 IN CEREBELLAR GRANULE CELLS
Hathaway, Hannah Allysum
Wroblewski, Jarda T
Glutamate is the predominant excitatory neurotransmitter in the mammalian brain, activating ionotropic and metabotropic glutamate (mGlu1) receptors. mGlu1 receptors are highly expressed in cerebellar granule cells, but relatively little is known about their function in these important cerebellar neurons. The studies in this thesis were design to investigate the function and signaling of mGlu1 receptors in the physiologically relevant model of cerebellar granule cells. In chapter 1, we report that activation of metabotropic glutamate (mGlu) 1 receptor is required for continued survival of granule cell cultures by showing that the protection mediated by three "depolarizing" stimuli (glutamate, NMDA, and K25) requires mGlu1 receptor activation. We also show that 7-day administration of the mGlu1 receptor antagonist JNJ16259685 to post-natal rats causes a significant decrease in weight of the cerebellum, implying that mGlu1 receptor activation may also be required for survival of cerebellar granule cells in vivo.In chapter 2, we pharmacologically characterize the neuroprotective action of mGlu1 receptors in cerebellar granule cells. We tested the ability of a panel of compounds to stimulate two mGlu1 receptor-mediated outcomes: (1) protection from decreased cell viability after withdrawal of trophic support and (2) G protein-mediated phosphoinositide (PI) hydrolysis. We report that the commonly used mGlu1 receptor ligands quisqualate, DHPG, and ACPD are completely biased towards PI hydrolysis and do not induce mGlu1 receptor-stimulated neuroprotection. On the other hand, endogenous compounds, including glutamate and aspartate, stimulate both responses. These results show that some commonly used mGlu1 receptor ligands are biased agonists, stimulating only a fraction of mGlu1 receptor-mediated responses in neurons.Finally, in chapter 3, we report that neuroprotective mGlu1 receptor signaling overcomes excitotoxic NMDA receptor signaling. Under pathophysiological conditions excess quantities of glutamate are released into the extracellular space and cause cell death via NMDA receptor-mediated excitotoxicity. Yet, in cerebellar granule cells, application of glutamate increases cell viability via activation of mGlu1 receptors. Here we report that when mGlu1 receptor activity is decreased, either by pharmacological blockade or by reduced receptor expression, glutamate application results in a decrease in granule cell viability that is blocked by antagonism of NMDA receptors.
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TOXIC SIGNALING OF METABOTROPIC GLUTAMATE 1 RECEPTOR IN CEREBELLAR NEURONS: INVOLVEMENT IN ABERRANT CELL CYCLE RE-ENTRY Takoudjou Dzomo, Guy Rodrigue (Georgetown University, 2012)Previously, we have shown that mGlu1 receptors play a dual role in neuronal apoptosis: mGlu1 receptor overexpression led to massive cell death while several mGlu1 receptor agonists protected neurons from this receptor-induced ...